Use of central cannabinoid receptor antagonists for the preparation of drugs

ABSTRACT

The invention relates to the use of a central cannabinoid receptor antagonist, by itself or in association with a compound for regulating metabolic disorders, especially a β 3 -adrenergic receptor agonist, for the preparation of drugs useful in the treatment of appetency disorders.

[0001] The present invention relates to a novel use of antagonists ofthe central cannabinoid receptors or so-called CB₁ receptors.

[0002] More particularly, the invention relates to the use of CB₁receptor antagonists for the preparation of drugs useful in thetreatment of appetency disorders. The purpose of drugs useful in thetreatment of appetency disorders is to regulate consumption desires,particularly desires to consume sugars, carbohydrates, alcohol or drugsand more generally to consume appetizing ingredients.

[0003] In the present description and in the claims, appetency disordersare understood as meaning:

[0004] disorders associated with a substance and especially abuse of asubstance and/or dependency on a substance,

[0005] disorders of food behaviors, especially those liable to causeexcess weight, irrespective of its origin, for example: bulimia,appetency for sugars, non-insulin-dependent diabetes.

[0006] Substances are understood as meaning appetizing ingredients suchas sugars, carbohydrates, alcohols or drugs.

[0007] The present invention therefore further relates to the use of aCB₁ receptor antagonist for the preparation of drugs useful in thetreatment of bulimia and obesity, including obesity associated with typeII diabetes (non-insulin-dependent diabetes), or more generally anydisease resulting in the patient becoming overweight, and in thetreatment of drug abuse or drug dependency.

[0008] Delta-9-tetrahydrocannabinol, or Δ⁹-THC, is the main activeconstituent extracted from Cannabis sativa (Tuner, 1985; in Marijuana,84, Ed. Harvey, D Y, IRL Press, Oxford).

[0009] The effects of cannabinoids are due to an interaction with highaffinity specific receptors coupled to G proteins. Two types ofreceptors are currently described: the CB₁ receptors, which are presentpredominantly in the central nervous system (Devane et al., MolecularPharmacology, 1988, 34, 605-613), and the CB₂ receptors, which arepresent in the immune system (Nye et al., The Journal of Pharmacologyand Experimental Therapeutics, 1985, 234, 784-791; Kaminski et al.,1992, Molecular Pharmacology, 42, 736-742; Munro et al., Nature, 1993,365, 61-65). Characterization of these receptors has been made possibleby the development of synthetic ligands such as CP 55,940 (J. Pharmacol.Exp. Ther., 1988, 247, 1046-1051) and WIN 55212-2 (J. Pharmacol. Exp.Ther., 1993, 264, 1352-1363) and, more recently, by the discovery of theselective CB₁ receptor antagonist SR 141716 A (M. Rinaldi-Carmona etal., FEBS Lett., 1994, 350, 240-244).

[0010] Families of compounds having an affinity for the cannabinoidreceptors have been described in several patents or patent applications,especially European patent application EP-576 357, which describespyrazole derivatives, and patent application WO 96/02248, whichdescribes especially benzofuran derivatives.

[0011] More particularly,N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide,also called SR 141716, of the formula

[0012] its pharmaceutically acceptable salts and their solvates aredescribed in European patent application EP-656 354 as CB₁ centralreceptor antagonists.

[0013] SR 141716 A is the hydrochloride of SR 141716.

[0014] It is known that delta-9-tetrahydrocannabinol, whoseinternational non-proprietary name is Dronabinol, is used in thetreatment of anorexia, especially in patients suffering from AIDS (J.Pain Symptom Manage., 1995, 10 (2), 89-97) or cancer (J. Palliat. Care,1994, 10 (1), 14-18).

[0015] It is further described that SR 141716 and its salts, which arecentral cannabinoid receptor antagonists, can be used in the treatmentof appetite disorders, especially as anorexigenic agents, and in thetreatment of disorders associated with the use of psychotropicsubstances.

[0016] Conventional anorexigenic agents cause an appetite reductionwhich is generally independent of the foods to be consumed.

[0017] Surprisingly, it has now been found that CB₁ receptor antagonistshave a specific property by acting electively on consumption behaviordisorders pertaining to appetizing substances.

[0018] Thus the administration of a CB₁ receptor antagonist makes itpossible to regulate the desire to consume non-essential food items suchas excess sugars, excess carbohydrates, alcohol or drugs.

[0019] In fact, after having conducted tests in animals, a novelbehavior of the animal has been noted: animal tests have revealed anovel behavior: the animal no longer shows spontaneous appetency for theingredient, for example sugar or alcohol, which usually brings pleasureto it. This lack of appetency also manifests itself when the animal hasbeen pretreated with a neuropeptide known to increase the appetite, forexample neuropeptide Y (NPY).

[0020] According to one of its aspects, the present invention relates tothe use of a CB₁ receptor antagonist for the preparation of drugs usefulin the treatment of appetency disorders.

[0021] The CB₁ receptor antagonists appropriate for the purposes of theinvention are particularly the compounds of the formula

[0022] in which:

[0023] R₁ is hydrogen, a fluorine, a hydroxyl, a (C₁-C₅)alkoxy, a(C₁-C₅)alkylthio, a hydroxy(C₁-C₅)alkoxy, a group —NR₁₀R₁₁, a cyano, a(C₁-C₅)alkylsulfonyl or a (C₁-C₅)alkylsulfinyl;

[0024] R₂ and R₃ are a (C₁-C₄)alkyl or, together with the nitrogen atomto which they are bonded, form a saturated or unsaturated 5- to10-membered heterocyclic radical which is unsubstituted ormonosubstituted or polysubstituted by a (C₁-C₃)alkyl or by a(C₁-C₃)alkoxy;

[0025] R₄, R₅, R₆, R₇, R₈ and R₉ are each independently hydrogen, ahalogen or a trifluoromethyl, and if R₁ is a fluorine, R₄, R₅, R₆, R₇,R₈ and/or R₉ can also be a fluoromethyl, with the proviso that at leastone of the substituents R₄ or R₇ is other than hydrogen; and

[0026] R₁₀ and R₁₁, are each independently hydrogen or a (C₁-C₅)alkyl,or R₁₀, and R₁₁, together with the nitrogen atom to which they arebonded, form a heterocyclic radical selected from pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl and piperazin-1-yl, which isunsubstituted or substituted by a (C₁-C₄)alkyl,

[0027] and their salts and their solvates.

[0028] More particularly, the present invention relates to the use ofN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide,its pharmaceutically acceptable salts and their solvates for thepreparation of drugs useful in the treatment of appetency disorders.

[0029] According to the present invention, the CB₁ receptor antagonistscan also be used in association with another active principle for thepreparation of drugs useful in the treatment of appetency disorders,especially in the treatment of disorders of food behaviors; it ispossible to use a pharmaceutical composition comprising a CB₁ receptorantagonist in association with a compound for regulating metabolicdisorders, especially a β₃-adrenergic receptor agonist, hereafter calleda β₃-agonist.

[0030] Thus the present invention further relates to pharmaceuticalcompositions containing a CB₁ receptor antagonist and a regulator ofmetabolic disorders, for example a hypolipemic, hypolydemic orlipolytic. More particularly, the present invention relates topharmaceutical compositions containing a CB₁ receptor antagonist and aβ₃-agonist.

[0031] β₃-agonists which can be used according to the present inventionare the compounds of the formula

[0032] in which:

[0033] X is hydrogen, a halogen, a trifluoromethyl or a (C₁-C₄)alkyl;

[0034] R is hydrogen or a methyl which is unsubstituted or substitutedby a carboxyl or an alkoxycarbonyl in which the alkoxy is (C₁-C₆),

[0035] and their pharmaceutically acceptable salts, indicated in EP 0211 721 and EP 0 303 546 as intestinal spasmolytics.

[0036] Among the compounds of formula (III), the following compounds:

[0037]2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;

[0038]2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)-ethanol;

[0039]2-[(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)ethanol;

[0040]2-[(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;

[0041](1R,2′RS)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;

[0042](1S,2′RS)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;

[0043](+)-(1R)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;

[0044](+)-(1S)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;

[0045](−)-(1R)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;

[0046](−)-(1S)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;

[0047]N-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamine;and

[0048]N-[(2R)-7-methoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamine,

[0049] and their pharmaceutically acceptable salts, are particularlyadvantageous.

[0050]N-[(2S)-7-Ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamine(SR 58611) and its pharmaceutically acceptable salts are veryparticularly advantageous, especially its salt with hydrochloric acid,SR 58611 A.

[0051] Other β₃-agonists which can be used according to the presentinvention are the compounds of the formula

[0052] in which:

[0053] n is 1,2 or 3;

[0054] A is a benzofuran-2-yl or a phenyl which is unsubstituted orsubstituted by one or two halogen atoms or by a (C₁-C₄)alkyl or atrifluoromethyl;

[0055] R′ is:

[0056] hydrogen;

[0057] a (C₁-C₆)alkyl;

[0058] a functional group selected from the following groups: hydroxyl;(C₁-C₆)alkoxy; (C₂-C₆)alkenyloxy; (C₂-C₆)alkynyloxy; (C₃-C₈)cycloalkoxy;(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; benzyloxy; phenoxy; mercapto;(C₁-C₆)alkylthio; (C₂-C₆)alkenylthio; (C₂-C₆)alkynylthio;(C₃-C₈)cycloalkylthio; (C₃ -C₈)cycloalkyl(C₁-C₆)alkylthio; benzylthio;phenylthio; (C₁-C₆)alkylsulfinyl; (C₂-C₆)alkenylsulfinyl;(C₂-C₆)alkynylsulfinyl; (C₃-C₈)cycloalkylsulfinyl;(C₃-C₈)cycloalkyl(C₁-C₆)alkylsulfinyl; benzylsulfinyl; phenylsulfinyl;(C₁-C₆)alkylsulfonyl; (C₂-C₆)alkenylsulfonyl; (C₂-C₆)alkynylsulfonyl;(C₃-C₈)cycloalkylsulfonyl; (C₃-C₈)cycloalkyl(C₁-C₆)alkylsulfonyl;benzylsulfonyl; phenylsulfonyl; cyano; nitro; amino which isunsubstituted or substituted by one or two identical or differentradicals selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, benzyl and phenylgroups; carboxyl; alkoxycarbonyl in which the alkoxy is (C₁-C₆);(C₂-C₆)alkenyloxycarbonyl; (C₂-C₆)alkenyloxycarbonyl;(C₃-C₈)cycloalkoxycarbonyl; (C₃-C₈)cycloalkyl(C₁-C₆)alkoxycarbonyl;benzyloxycarbonyl; phenoxycarbonyl; or carbamoyl which is unsubstitutedor substituted on the amino group by one or two identical or differentradicals selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, benzyl and phenylgroups;

[0059] a group R′″ selected from the following groups: (C₁-C₆)alkylsubstituted by a functional group; (C₂-C₆)alkenyl substituted by afunctional group; (C₂-C₆)alkynyl substituted by a functional group;phenyl(C₁-C₆)alkyl substituted on the phenyl by a (C₁-C₆)alkyl or by afunctional group; phenyl(C₂-C₆)alkenyl substituted on the phenyl by a(C₁-C₆)alkyl or by a functional group; phenyl(C₂-C₆)alkynyl substitutedon the phenyl by a (C₁-C₆)alkyl or by a functional group; benzylsubstituted on the phenyl by a (C₁-C₆)alkyl or by a functional group;and phenyl which is unsubstituted or substituted by a (C₁-C₆)alkyl or bya functional group, the functional group being as defined above;

[0060] a group O—R′″, S—R′″, SO—R′″ or SO₂—R′″, in which R′″ is asdefined above;

[0061] a group NR′″R⁰, in which R′″ is as defined above and R⁰ ishydrogen or is as defined above for R′″, or R′″ and R⁰, together withthe nitrogen to which they are bonded, form a group selected frompyrrolidino, piperidino and morpholino groups;

[0062] a group COOR′″ or a group CO—SR′″, in which R′″ is as definedabove;

[0063] a group CONR′″R⁰, in which R′″ is as defined above and R⁰ ishydrogen or is as defined above for R′″, or R′″ and R⁰, together withthe nitrogen to which they are bonded, form a group selected frompyrrolidino, piperidino and morpholino groups;

[0064] a group SO₂NR′″R⁰, in which R′″ is as defined above and R⁰ ishydrogen or is as defined above for R′″, or R′″ and R⁰, together withthe nitrogen to which they are bonded, form a group selected frompyrrolidino, piperidino and morpholino groups;

[0065] R″ is hydrogen; a halogen; a (C₁-C₆)alkyl; a functional group asdefined above; a group OR′″, R′″ being as defined above; a group COOR′″,R′″ being as defined above; or a group CONR′″R⁰, in which R′″ is asdefined above and R⁰ is hydrogen or is as defined above for R′″, or R′″and R⁰, together with the nitrogen to which they are bonded, form agroup selected from pyrrolidino, piperidino and morpholino groups;

[0066] W is a direct bond or an oxygen atom;

[0067] X′ is hydrogen, a (C₁-C₆)alkyl or a (C₁-C₆)alkylcarbonyl;

[0068] Y is hydrogen or a group A′—CH(OH)—CH₂—, A′ being identical to Abut other than benzofuran-2-yl; or

[0069] X′ and Y, taken together, form a methylene group optionallysubstituted by an alkoxycarbonyl in which the alkoxy is (C₁-C6); anethylene group optionally substituted by an oxo group; or a1,3-propylene group;

[0070] Z is hydrogen or a (C₁-C₆)alkyl,

[0071] and their pharmaceutically acceptable salts, indicated in EP 0255 415 as intestinal spasmolytics.

[0072] Other β₃-agonists which can also be used according to the presentinvention are the compounds of the formula

[0073] in which:

[0074] E is hydrogen, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a phenyl, anitro, a halogen atom or a trifluoromethyl;

[0075] L is hydrogen, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a phenyl, a nitroor a halogen atom; or E and L together are a group —CH═CH—CH═CH— or—CH₂—CH₂—CH₂—CH₂—; and

[0076] G is hydrogen, a chlorine atom, a hydroxyl or a group OG′, inwhich G′ is a (C₁-C₄)alkyl which is unsubstituted or substituted by ahydroxyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, carboxyl or(C₃-C₇)cycloalkyl; a (C₃-C₇)cycloalkyl; or a (C₂-C₄)alkanoyl,

[0077] and their pharmaceutically acceptable salts, indicated in EP 0436 435 as intestinal spasmolytics.

[0078] Among the compounds of formula (V),N-[(2R)-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine(SR 59104),N-[(2R)-(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine(SR 59119) and their pharmaceutically acceptable salts are particularlyadvantageous compounds.

[0079] Other advantageous β₃-agonists according to the present inventionare the compound BRL 35135 described in EP 23385; the compound CL 316243described in U.S. Pat. No. 5 061 727; the compound AZ 002 described inEP 218440; the compound BMS 187257 described in U.S. Pat. No. 5,321,036;the compound ZD 7114 described in EP 473 285; the compound RO 40-2148described in Am. J. Clin. Nutr., 1992, 55 (1, Suppl.), 249S-251S; andthe products described in the following patents/patent applications: WO96/35671, WO 96/35670, WO 96/16038, WO 96/04233, WO 95/33724, WO95/29159, EP 659737, WO 95/04047, EP 516349, EP 473285, EP 23385, EP21636, EP 7205, JP 08198866, JP 08165276, JP 08157470, WO 96/16938, EP714883, WO 96/04234, U.S. Pat. Nos. 5,488,064, 5,482,971, 5,491,134, WO95/29159, WO 95/33724, ZA 9409874, WO 95/29903, U.S. Pat. No. 5,461,163,WO 95/25104, EP 659737, JP 07112958, WO 95/8527, WO 95/07284, JP07025756, WO 95/03289, WO 95/04047, WO 95/01170, WO 94/29290, U.S. Pat.No. 5,373,020, JP 06293664, WO 94/12166 and U.S. Pat. No. 5,451,677.

[0080] For its use as a drug, a CB₁ receptor antagonist compound, byitself or in association with a β₃-agonist, must be formulated as apharmaceutical composition.

[0081] In the pharmaceutical compositions of the present invention fororal, sublingual, subcutaneous, intramuscular, intravenous, transdermal,local or rectal administration, the active principle, by itself or inassociation with another active principle, can be administered toanimals and humans in unit forms of administration mixed withconventional pharmaceutical carriers. The appropriate unit forms ofadministration include oral forms such as tablets, gelatin capsules,powders, granules and solutions or suspensions to be taken orally,sublingual and buccal forms of administration, aerosols, implants,subcutaneous, intramuscular, intravenous, intranasal or intraocularforms of administration and rectal forms of administration.

[0082] In the pharmaceutical compositions of the present invention, theactive principle or active principles are generally formulated in dosageunits. The dosage unit contains from 0.5 to 1000 mg, advantageously from1 to 500 mg and preferably from 2 to 200 mg of CB₁ receptor antagonistper dosage unit for daily administration.

[0083] In cases where 2 active principles are associated, the dosageunit contains from 0.5 to 600 mg, advantageously from 1 to 400 mg andpreferably from 2 to 200 mg of CB₁ receptor antagonist compound and from0.5 to 600 mg, advantageously from 2 to 400 mg and preferably from 10 to250 mg of the other active principle, especially a β3-agonist.

[0084] When a solid composition is prepared in the form of tablets, awetting agent such as sodium laurylsulfate can be added to themicronized or non-micronized active principle(s) and the whole is mixedwith a pharmaceutical vehicle such as silica, starch, lactose, magnesiumstearate, talcum or the like. The tablets can be coated with sucrose, avariety of polymers or other appropriate substances, or else they can betreated so as to have a sustained or delayed activity and so as torelease a predetermined amount of active principle continuously.

[0085] A preparation in the form of gelatin capsules is obtained bymixing the active principle or active principles with a diluent, such asa glycol or a glycerol ester, and incorporating the resulting mixtureinto soft or hard gelatin capsules.

[0086] A preparation in the form of a syrup or elixir can contain theactive principle or active principles together with a sweetener, whichis preferably calorie-free, methylparaben and propylparaben asantiseptics, a flavoring and an appropriate color.

[0087] The water-dispersible powders or granules can contain the activeprinciple or active principles mixed with dispersants or wetting agentsor with suspending agents such as polyvinylpyrrolidone or polyvidone, aswell as with sweeteners or taste correctors.

[0088] Rectal administration is effected using suppositories, which areprepared with binders melting at the rectal temperature, for examplecocoa butter or polyethylene glycols.

[0089] Parenteral administration is effected using aqueous suspensions,isotonic saline solutions or injectable sterile solutions containingpharmacologically compatible dispersants and/or solubilizing agents, forexample propylene glycol or butylene glycol.

[0090] Thus, to prepare an aqueous solution for intravenous injection,it is possible to use a cosolvent, for example an alcohol such asethanol or a glycol such as polyethylene glycol or propylene glycol, anda hydrophilic surfactant such as Tween® 80. To prepare an oily solutionfor intramuscular injection, the active principle can be solubilizedwith a triglyceride or a glycerol ester.

[0091] Transdermal administration can be effected using patches inmultilaminar form or with a reservoir in which the active principle isin alcoholic solution.

[0092] The active principle or active principles can also be formulatedas microcapsules or microspheres, optionally with one or more carriersor additives.

[0093] The active principle or active principles can also be presentedin the form of complexes with a cyclodextrin, for example α-, β- orγ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

[0094] Among the sustained release forms useful in the case of chronictreatments, it is possible to use implants. These can be prepared in theform of an oily suspension or in the form of a suspension ofmicrospheres in an isotonic medium.

[0095] According to another aspect of the invention, the CB₁ receptorantagonist and the regulator of metabolic disorders, especially theβ₃-agonist, can be administered simultaneously, sequentially or over aperiod of time in the treatment of appetency disorders, especially inthe treatment of disorders of food behaviors.

[0096] The invention therefore further relates to a kit for thetreatment of appetency disorders by the administration, simultaneously,sequentially or over a period of time, of a CB₁ receptor antagonist anda regulator of metabolic disorders, especially a β₃-agonist, in whichkit said CB₁ receptor antagonist and said regulator of metabolicdisorders, especially said β₃-agonist, are in separate compartments andoptionally in different packagings.

[0097] More particularly, said kit containsN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide,one of its pharmaceutically acceptable salts or one of their solvates,andN-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamineor one of its pharmaceutically acceptable salts.

[0098] According to another of its aspects, the invention furtherrelates to a method of treating appetency disorders, especially a methodof treating disorders of food behaviors, which consists inadministering, to a subject in need thereof, a (therapeutically)effective amount of a CB₁ receptor antagonist as defined above. Said CB₁receptor antagonist can advantageously be used in association with aregulator of metabolic disorders, especially a β₃ agonist, as definedabove. In particular, the CB₁ receptor antagonist and the regulator ofmetabolic disorders can be administered simultaneously, sequentially orover a period of time.

[0099] Test No. 1: Effect of SR 141716 A on the Intake of a SucroseSolution in Rats

[0100] The experiment is performed according to W. C. Lynch et al.,Physiol. Behav., 1993, 54, 877-880.

[0101] Male Sprague-Dawley rats weighing 190 to 210 g are under a normallight cycle (from 7 am to 7 pm) and receive water and food ad libitum.

[0102] For 6 days, between 11 am and 3 pm, the food and the waterbottles are withdrawn and the rats are given a 5% sucrose solution todrink.

[0103] Rats drinking less than 3 g of sucrose solution are eliminated.

[0104] On the seventh day the test is carried out according to thefollowing procedure:

[0105] 9 am: withdrawal of food,

[0106] 10 am: oral administration of SR 141716 A,

[0107] 11 am =T0: introduction of bottles containing a weighed sucrosesolution, T0+1 hour, T0+2 hours, T0+3 hours, T0+4 hours: measurement ofthe sucrose consumption by weighing of the bottles. TABLE 1 TreatmentNumber of Consumption of sucrose solution in g po rats 1 hour 2 hours 3hours 4 hours Vehicle 8 11.33 ± 17.74 ± 22.50 ± 28.34 ±   2 ml/kg 2.504.00 4.83 5.01 SR 141716 A 6  5.18 ±  9.18 ± 12.49 ± 16.10 ± 0.3 mg/kg1.61 2.12 4.47 3.95 SR 141716 A 6 3.27* ± 3.61** ±  5.65* ± 7.43** ±   1 mg/kg 1.40 1.40 2.23 2.81 SR 141716 A 6 2.95* ± 5.41* ± 6.96* ±8.58** ±    3 mg/kg 1.20 1.33 2.15 2.92

[0108] It is seen from the results reported in TABLE 1 that theadministration of SR 141716 A very considerably reduces the consumptionof aqueous sugar solution at or above a dose of 0.3 mg/kg.

[0109] Test No. 2: Effect of SR 141716 A on the Consumption of anAlcohol Solution in Mice

[0110] Male C 57 BL 6 mice (Iffa-Credo) are isolated on the day of theirarrival in an animal housing under a reverse cycle (night from 10 am to10 pm) with 2 bottles filled with water. After 1 week, one of thebottles of water is replaced with a bottle filled with a 10% alcoholsolution for 6 hours of the test. Each day, 30 minutes before the bottleof alcohol is introduced, the mice are treated subcutaneously with SR141716 A. The amounts of alcohol and water consumed are measured after 6hours. The test is repeated for 4 days. TABLE 2 Amount of Treatmentmg/kg/sc Number of Amount of alcohol water SR 141716 A mice consumed ing on D4 consumed in g Vehicle 20 1.9 ± 0.1 1.1 ± 0.1 0.1 10 1.4 ± 0.21.1 ± 0.3 0.3 10 1.3 ± 0.2 1.1 ± 0.3 1 10  1.1 ± 0.2** 1.3 ± 0.1 3 10 1.0 ± 0.2** 1.6 ± 0.3

[0111] The results show that the alcohol consumption decreases verysubstantially for the treated animals: from 1.9±0.1 g for an untreatedanimal to 1.0±0.2 g for an animal receiving 3 mg/kg of SR 141716 A; thewater consumption increased in parallel: from 1.1±0.1 to 1.6±0.3 g.

EXAMPLE 1

[0112] Gelatin Capsule Containing a 1 mg Dose of CB₁ Receptor AntagonistMicronized SR 141716 1.00 mg Corn starch 51.00 mg Lactose monohydrate103.33 mg Polyvidone 4.30 mg Sodium laurylsulfate 0.17 mg Crosslinkedsodium carboxymethyl cellulose 8.50 mg Purified water: QS for wetgranulation Magnesium stearate 1.70 mg

[0113] For a no. 3 opaque white gelatin capsule filled to 170 mg.

EXAMPLE 2

[0114] Gelatin Capsule Containing a 10 mg Dose of CB₁ ReceptorAntagonist Micronized SR 141716 A 10.00 mg Corn starch 51.00 mg Lactosemonohydrate 94.33 mg Polyvidone 4.30 mg Sodium laurylsulfate 0.17 mgCrosslinked sodium carboxymethyl cellulose 8.50 mg Purified water: QSfor wet granulation Magnesium stearate 1.70 mg

[0115] For a no. 3 opaque white gelatin capsule filled to 170 mg.

EXAMPLE 3

[0116] Gelatin Capsule Containing a 30 mg Dose of CB₁ ReceptorAntagonist Micronized SR 141716 30.00 mg Corn starch 51.00 mg Lactosemonohydrate 74.33 mg Polyvidone 4.30 mg Sodium laurylsulfate 0.17 mgCrosslinked sodium carboxymethyl cellulose 8.50 mg Purified water: QSfor wet granulation Magnesium stearate 1.70 mg

[0117] For a no. 3 opaque white gelatin capsule filled to 170 mg.

EXAMPLE 4

[0118] Tablet Containing a 30 mg Dose of CB₁ Receptor AntagonistMicronized SR 141716 30.00 mg Lactose monohydrate QS Corn starch 40.00mg Hydroxypropyl methyl cellulose 6 cP 5.00 mg Purified water: QS forwet granulation Crosslinked sodium carboxymethyl cellulose 10.00 mgMagnesium stearate 2.00 mg

[0119] For a finished tablet of 200 mg.

EXAMPLE 5

[0120] Tablet Containing 30 mg of CB₁ Receptor Antagonist and 200 mg ofβ₃-Agonist Micronized SR 141716 30.00 mg SR 58611 A expressed as thebase 200.00 mg Lactose monohydrate QS Polyvidone 15.00 mg Purifiedwater: QS for wet granulation Crosslinked sodium carboxymethyl cellulose10.00 mg Magnesium stearate 5.00 mg

[0121] For a finished tablet of 500 mg.

EXAMPLE 6

[0122] Tablet Containing 10 mg of CB₁ Receptor Antagonist and 100 mg ofβ₃-Agonist Micronized SR 141716 10.00 mg SR 58611 A expressed as thebase 100.00 mg Corn starch 30 mg Lactose monohydrate QS Hydroxypropylmethyl cellulose 6 cP 5.00 mg Purified water: QS for wet granulationSodium carboxymethyl starch 6.00 mg Magnesium stearate 3.00 mg

[0123] For a finished tablet of 300 mg.

1. Use of a CB₁ receptor antagonist for the preparation of drugs usefulin the treatment of appetency disorders.
 2. Use according to claim 1 forthe preparation of drugs intended for regulating consumption desires. 3.Use according to claim 1 for the preparation of drugs useful in thetreatment of disorders associated with a substance.
 4. Use according toclaim 1 for the preparation of drugs useful in the treatment ofdisorders of food behaviors.
 5. Use according to claim 1 for thepreparation of drugs useful in the treatment of obesity.
 6. Useaccording to claim 5 for the preparation of drugs useful in thetreatment of obesity associated with non-insulin-dependent diabetes. 7.Use according to claim 1 for the preparation of drugs useful in thetreatment of any disease resulting in the patient becoming overweight.8. Use according to claim 1 for the preparation of drugs useful in thetreatment of bulimia.
 9. Use according to claim 1 for the preparation ofdrugs useful in the treatment of drug abuse or drug dependency.
 10. Useaccording to any one of claims 1 to 9, characterized in that the CB₁receptor antagonist is a compound of the formula

in which: R₁ is hydrogen, a fluorine, a hydroxyl, a (C₁-C₅)alkoxy, a(C₁-C₅)alkylthio, a hydroxy(C₁-C₅)alkoxy, a group —NR₁₀R₁₁, a cyano, a(C₁-C₅)alkylsulfonyl or a (C₁-C₅)alkylsulfinyl; R₂ and R₃ are a(C₁-C₄)alkyl or, together with the nitrogen atom to which they arebonded, form a saturated or unsaturated 5- to 10-membered heterocyclicradical which is unsubstituted or monosubstituted or polysubstituted bya (C₁-C₃)alkyl or by a (C₁-C₃)alkoxy; R₄, R₅, R₆, R₇, R₈ and R₉ are eachindependently hydrogen, a halogen or a trifluoromethyl, and if R₁ is afluorine, R₄, R₅, R₆, R₇, R₈ and/or R₉ can also be a fluoromethyl, withthe proviso that at least one of the substituents R₄ or R₇ is other thanhydrogen; R₁₀ and R₁₁ are each independently hydrogen or a (C₁-C₅)alkyl,or R₁₀ and R₁₁, together with the nitrogen atom to which they arebonded, form a heterocyclic radical selected from pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl and piperazin-1-yl, which isunsubstituted or substituted by a (C₁-C₄)alkyl, one of its salts or oneof their solvates.
 11. Use according to claim 10, characterized in thatthe CB₁ receptor antagonist isN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide,one of its pharmaceutically acceptable salts or one of their solvates.12. Use according to any one of claims 1 to 8, 10 or 11, characterizedin that the CB₁ receptor antagonist is associated with a regulator ofmetabolic disorders.
 13. Use according to claim 12, characterized inthat said regulator of metabolic disorders is a β₃-agonist.
 14. Useaccording to claim 13, characterized in that said β₃-agonist is acompound of the formula

in which: X is hydrogen, a halogen, a trifluoromethyl or a (C₁-C₄)alkyl;and R is hydrogen or a methyl which is unsubstituted or substituted by acarboxyl or an alkoxycarbonyl in which the alkoxy is (C₁-C₆), or one ofits pharmaceutically acceptable salts.
 15. Use according to claim 14,characterized in that said β₃-agonist isN-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamineor one of its pharmaceutically acceptable salts.
 16. Use according toclaim 13, characterized in that said β₃-agonist is a compound of theformula

in which: n is 1,2 or 3; A is a benzofuran-2-yl or a phenyl which isunsubstituted or substituted by one or two halogen atoms or by a(C₁-C₄)alkyl or a trifluoromethyl; R′ is: hydrogen; a (C₁-C₆)alkyl; afunctional group selected from the following groups: hydroxyl;(C₁-C₆)alkoxy; (C₂-C₆)alkenyloxy; (C₂-C₆)alkynyloxy; (C₃-C₈)cycloalkoxy;(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; benzyloxy; phenoxy; mercapto;(C₁-C₆)alkylthio; (C₂-C₆)alkenylthio; (C₂-C₆)alkynylthio;(C₃-C₈)cycloalkylthio; (C₃-C₈)cycloalkyl(C₁-C₆)alkylthio; benzylthio;phenylthio; (C₁-C6)alkylsulfinyl; (C₂-C₆)alkenylsulfinyl;(C₂-C₆)alkynylsulfinyl; (C₃-C₈)cycloalkylsulfinyl;(C₃-C₈)cycloalkyl(C₁-C₆)alkylsulfinyl; benzylsulfinyl; phenylsulfinyl;(C₁-C₆)alkylsulfonyl; (C₂-C₆)alkenylsulfonyl; (C₂-C6)alkynylsulfonyl;(C₃-C₈)cycloalkylsulfonyl; (C₃-C₈)cycloalkyl(C₁-C₆)alkylsulfonyl;benzylsulfonyl; phenylsulfonyl; cyano; nitro; amino which isunsubstituted or substituted by one or two identical or differentradicals selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C8)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, benzyl and phenylgroups; carboxyl; alkoxycarbonyl in which the alkoxy is (C₁-C₆);(C₂-C₆)alkynyloxycarbonyl; (C₂-C₆)alkenyloxycarbonyl;(C₃-C₈)cycloalkoxycarbonyl; (C₃-C₈)cycloalkyl(C₁-C₆)alkoxycarbonyl;benzyloxycarbonyl; phenoxycarbonyl; or carbamoyl which is unsubstitutedor substituted on the amino group by one or two identical or differentradicals selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, benzyl and phenylgroups; a group R′″ selected from the following groups: (C₁-C₆)alkylsubstituted by a functional group; (C₂-C₆)alkenyl substituted by afunctional group; (C₂-C₆)alkynyl substituted by a functional group;phenyl(C₁-C₆)alkyl substituted on the phenyl by a (C₁-C₆)alkyl or by afunctional group; phenyl(C₂-C₆)alkenyl substituted on the phenyl by a(C₁-C₆)alkyl or by a functional group; phenyl(C₂-C₆)alkynyl substitutedon the phenyl by a (C₁-C₆)alkyl or by a functional group; benzylsubstituted on the phenyl by a (C₁-C₆)alkyl or by a functional group;and phenyl which is unsubstituted or substituted by a (C₁-C₆)alkyl or bya functional group, the functional group being as defined above; a groupO—R′″, S—R′″, SO—R′″, or SO₂—R′″, in which R′″ is as defined above; agroup NR′″R⁰, in which R′″ is as defined above and R⁰ is hydrogen or isas defined above for R′″, or R′″ and R⁰, together with the nitrogen towhich they are bonded, form a group selected from pyrrolidino,piperidino and morpholino groups; a group COOR′″ or a group CO—SR′″, inwhich R′″ is as defined above; a group CONR′″R⁰, in which R′″ is asdefined above and R⁰ is hydrogen or is as defined above for R′″, or R′″and R⁰, together with the nitrogen to which they are bonded, form agroup selected from pyrrolidino, piperidino and morpholino groups; agroup SO₂NR′″R⁰, in which R′″ is as defined above and R⁰ is hydrogen oris as defined above for R′″, or R′″ and R⁰, together with the nitrogento which they are bonded, form a group selected from pyrrolidino,piperidino and morpholino groups; R′ is hydrogen; a halogen; a(C₁-C₆)alkyl; a functional group as defined above; a group OR′″, R′″being as defined above; a group COOR′″, R′″ being as defined above; or agroup CONR′″R⁰, in which R′″ is as defined above and R⁰ is hydrogen oris as defined above for R′″, or R′″ and R⁰, together with the nitrogento which they are bonded, form a group selected from pyrrolidino,piperidino and morpholino groups; W is a direct bond or an oxygen atom;X′ is hydrogen, a (C₁-C₆)alkyl or a (C₁-C₆)alkylcarbonyl; Y is hydrogenor a group A′—CH(OH)—CH₂—, A′ being identical to A but other thanbenzofuran-2-yl; or X′ and Y, taken together, form a methylene groupoptionally substituted by an alkoxycarbonyl in which the alkoxy is(C₁-C₆); an ethylene group optionally substituted by an oxo group; or a1,3-propylene group; Z is hydrogen or a (C₁-C₆)alkyl, or one of itspharmaceutically acceptable salts.
 17. Use according to claim 13,characterized in that said β₃-agonist is a compound of the formula

in which: E is hydrogen, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a phenyl, anitro, a halogen atom or a trifluoromethyl; L is hydrogen, a(C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a phenyl, a nitro or a halogen atom; or Eand L together are a group —CH═CH—CH═CH— or —CH₂—CH₂—CH₂—CH₂—; and G ishydrogen, a chlorine atom, a hydroxyl or a group OG′, in which G′ is a(C₁-C₄)alkyl which is unsubstituted or substituted by a hydroxyl,(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, carboxyl or (C₃-C₇)cycloalkyl; a(C₃-C₇)cycloalkyl; or a (C₂-C₄)alkanoyl, or one of its pharmaceuticallyacceptable salts.
 18. Use according to claim 13, characterized in thatthe CB₁ receptor antagonist isN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide,one of its pharmaceutically acceptable salts or one of their solvatesand the β₃-agonist isN-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamineor one of its pharmaceutically acceptable salts.
 19. A pharmaceuticalcomposition containing a CB₁ receptor antagonist and a regulator ofmetabolic functions with a pharmaceutical excipient.
 20. Apharmaceutical composition according to claim 19, characterized in thatsaid regulator of metabolic functions is a β₃-agonist.
 21. Apharmaceutical composition according to claim 19 or 20, characterized inthat the CB₁ receptor antagonist is a compound of the formula

in which: R₁ is hydrogen, a fluorine, a hydroxyl, a (C₁-C₅)alkoxy, a(C₁-C₅)alkylthio, a hydroxy(C₁-C₅)alkoxy, a group —NR₁₀R₁₁, a cyano, a(C₁-C₅)alkylsulfonyl or a (C₁-C₅)alkylsulfinyl; R₂ and R₃ are a(C₁-C₄)alkyl or, together with the nitrogen atom to which they arebonded, form a saturated or unsaturated 5- to 10-membered heterocyclicradical which is unsubstituted or monosubstituted or polysubstituted bya (C₁-C₃)alkyl or by a (C₁-C₃)alkoxy; R₄, R₅, R₆, R₇, R₈ and R₉ are eachindependently hydrogen, a halogen or a trifluoromethyl, and if R₁ is afluorine, R₄, R₅, R₆, R₇, R₈ and/or R₉ can also be a fluoromethyl, withthe proviso that at least one of the substituents R₄ or R₇ is other thanhydrogen; R₁₀ and R₁₁ are each independently hydrogen or a (C₁-C₅)alkyl,or R₁₀ and R₁₁, together with the nitrogen atom to which they arebonded, form a heterocyclic radical selected from pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl and piperazin-1-yl, which isunsubstituted or substituted by a (C₁-C₄)alkyl, one of its salts or oneof their solvates.
 22. A pharmaceutical composition according to claim21, characterized in that the CB₁ receptor antagonist isN-piperidino-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, one of itspharmaceutically acceptable salts or one of their solvates.
 23. Apharmaceutical composition according to any one of claims 20 to 22,characterized in that the β₃-agonist is a compound of the formula

in which: X is hydrogen, a halogen, a trifluoromethyl or a (C₁-C₄)alkyl;R is hydrogen or a methyl which is unsubstituted or substituted by acarboxyl or an alkoxycarbonyl in which the alkoxy is (C₁-C₆), or one ofits pharmaceutically acceptable salts.
 24. A pharmaceutical compositionaccording to any one of claims 20 to 22, characterized in that theβ₃-agonist is a compound of the formula

in which: n is 1,2 or 3; A is a benzofuran-2-yl or a phenyl which isunsubstituted or substituted by one or two halogen atoms or by a(C₁-C₄)alkyl or a trifluoromethyl; R′ is: hydrogen; a (C₁-C₆)alkyl; afunctional group selected from the following groups: hydroxyl;(C₁-C₆)alkoxy; (C₂-C₆)alkenyloxy; (C₂-C₆)alkynyloxy; (C₃-C₈)cycloalkoxy;(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; benzyloxy; phenoxy; mercapto;(C₁-C₆)alkylthio; (C₂-C₆)alkenylthio; (C₂-C₆)alkynylthio;(C₃-C₈)cycloalkylthio; (C₃-C₈)cycloalkyl(C₁-C₆)alkylthio; benzylthio;phenylthio; (C₁-C₆)alkylsulfinyl; (C₂-C₆)alkenylsulfinyl;(C₂-C₆)alkynylsulfinyl; (C₃-C₈)cycloalkylsulfinyl; (C₃-C₈)cycloalkyl(C₁-C6)alkylsulfinyl; benzylsulfinyl; phenylsulfinyl;(C₁-C₆)alkylsulfonyl; (C₂-C₆)alkenylsulfonyl; (C₂-C₆)alkynylsulfonyl;(C₃-C₈)cycloalkylsulfonyl; (C₃-C₈)cycloalkyl(C₁-C₆)alkylsulfonyl;benzylsulfonyl; phenylsulfonyl; cyano; nitro; amino which isunsubstituted or substituted by one or two identical or differentradicals selected from (C₁ -C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C1-C₆)alkyl, benzyl and phenylgroups; carboxyl; alkoxycarbonyl in which the alkoxy is (C₁-C₆);(C₂-C₆)alkenyloxycarbonyl; (C₂-C₆)alkynyloxycarbonyl;(C₃-C₈)cycloalkoxycarbonyl; (C₃-C₈)cycloalkyl(C₁-C₆)alkoxycarbonyl;benzyloxycarbonyl; phenoxycarbonyl; and carbamoyl which is unsubstitutedor substituted on the amino group by one or two identical or differentradicals selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, benzyl and phenylgroups; a group R′″ selected from the following groups: (C₁-C₆)alkylsubstituted by a functional group; (C₂-C₆)alkenyl substituted by afunctional group; (C₂-C₆)alkynyl substituted by a functional group;phenyl(C₁-C₆)alkyl substituted on the phenyl by a (C₁-C₆)alkyl or by afunctional group; phenyl(C₂-C₆)alkenyl substituted on the phenyl by a(C₁-C₆)alkyl or by a functional group; phenyl(C₂-C₆)alkennyl substitutedon the phenyl by a (C₁-C₆)alkyl or by a functional group; benzylsubstituted on the phenyl by a (C₁-C₆)alkyl or by a functional group;and phenyl which is unsubstituted or substituted by a (C₁-C₆)alkyl or bya functional group, the functional group being as defined above; a groupO—R′″, S—R′″, SO—R′″ or SO₂—R′″, in which R′″is as defined above; agroup NR′″R⁰, in which R′″ is as defined above and R⁰ is hydrogen or isas defined above for R′″, or R′″ and R⁰, together with the nitrogen towhich they are bonded, form a group selected from pyrrolidino,piperidino and morpholino groups; a group COOR′″ or a group CO—SR′″, inwhich R′″ is as defined above; a group CONR′″R⁰, in which R′″ is asdefined above and R⁰ is hydrogen or is as defined above for R′″, or R′″and R⁰, together with the nitrogen to which they are bonded, form agroup selected from pyrrolidino, piperidino and morpholino groups; agroup SO₂NR′″R⁰, in which R′″ is as defined above and R⁰ is hydrogen oris as defined above for R′″, or R′″ and R⁰, together with the nitrogento which they are bonded, form a group selected from pyrrolidino,piperidino and morpholino groups; R″ is hydrogen; a halogen; a(C₁-C₆)alkyl; a functional group as defined above; a group OR′″, R′″being as defined above; a group COOR′″, R′″ being as defined above; or agroup CONR′″R⁰, in which R′″ is as defined above and R⁰ is hydrogen oris as defined above for R′″, or R′″ and R⁰, together with the nitrogento which they are bonded, form a group selected from pyrrolidino,piperidino and morpholino groups; W is a direct bond or an oxygen atom;X′ is hydrogen, a (C₁-C₆)alkyl or a (C₁-C₆)alkylcarbonyl; Y is hydrogenor a group A′—CH(OH)—CH₂—, A′ being identical to A but other thanbenzofuran-2-yl; or X′ and Y, taken together, form a methylene groupoptionally substituted by an alkoxycarbonyl in which the alkoxy is(C₁-C₆); an ethylene group optionally substituted by an oxo group; or a1,3-propylene group; Z is hydrogen or a (C₁-C₆)alkyl, or one of itspharmaceutically acceptable salts.
 25. A pharmaceutical compositionaccording to any one of claims 20 to 22 wherein the β₃-agonist is acompound of the formula

in which: E is hydrogen, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a phenyl, anitro, a halogen atom or a trifluoromethyl; L is hydrogen, a(C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a phenyl, a nitro or a halogen atom; or Eand L together are a group —CH═CH—CH═CH— or —CH₂—CH₂—CH₂—CH₂—; and G ishydrogen, a chlorine atom, a hydroxyl or a group OG′, in which G′ is a(C₁-C₄)alkyl which is unsubstituted or substituted by a hydroxyl,(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, carboxyl or (C₃-C₇)cycloalkyl; a(C₃-C₇)cycloalkyl; or a (C₂-C₄)alkanoyl, or one of its pharmaceuticallyacceptable salts.
 26. A pharmaceutical composition according to claim23, characterized in that the β₃ agonist isN-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamineor one of its pharmaceutically acceptable salts.
 27. A pharmaceuticalcomposition according to any one of claims 20 to 26 containing from 0.5to 600 mg of CB₁ receptor antagonist and from 0.5 to 600 mg ofβ₃-agonist.
 28. A pharmaceutical composition according to claim 27containing from 1 to 400 mg of CB₁ receptor antagonist and from 2 to 400mg of β₃-agonist.
 29. A pharmaceutical composition according to claim 28containing from 2 to 200 mg of CB₁ receptor antagonist and from 10 to250 mg of β₃-agonist.
 30. A kit for the treatment of appetencydisorders, which contains: a CB₁ receptor antagonist, and a regulator ofmetabolic disorders, said active principles being in separatecompartments and being intended to be administered simultaneously,sequentially or over a period of time.
 31. A kit according to claim 30in which said regulator of metabolic disorders is a β₃-agonist.
 32. Akit according to claim 30 or 31 in which said CB₁ receptor antagonist isN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, one of itspharmaceutically acceptable salts or one of their solvates and saidβ₃-agonist isN-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamineor one of its pharmaceutically acceptable salts.
 33. A kit according toany one of claims 30 to 32 in which said active principles are indifferent packagings.
 34. Use according to claim 1 for the preparationof a drug useful for regulating the desire to consume non-essential fooditems.
 35. Use according to claim 34 in which the non-essential fooditems are excess sugars, excess carbohydrates, alcohol and drugs. 36.Use of a CB₁ receptor antagonist for the preparation of a drug useful tosuppress spontaneous appetency for a food item which usually bringspleasure.
 37. Use according to claim 36 in which the food item foundpleasurable is alcohol or sugar.
 38. Use according to any one of claims34 to 37 in which the CB₁ receptor antagonist isN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide,one of its pharmaceutically acceptable salts or one of their solvates.